Osteoporosis remains a major challenge to the maintenance of health and quality of life in an aging population. Among the most promising and least exploited therapeutic interventions are those treatments designed to increase bone density. The selection and validation of targets that can be manipulated to achieve this anabolic effect depends on an increasing amount of information relating to bone formation. Progenra has completed the construction and validation for high throughput screening of an assay for Praja1, an E3 ligase responsible for proteasomal degradation of Dlxin-1/MAGE-D1, a coactivator of the transcriptional activator Dlx5. Dlx5 is associated with programmed bone formation. Thus, selective inhibitors of this E3 ligase are hypothesized to increase bone density. Collections of small molecules, as well as plant and marine organism extracts from the NCI, will be screened to find potent and selective inhibitors of Praja1 activity. Lead compounds will be identified from among the hits, and fractionation of active extracts will be guided by the assay, to identify active principles. Among the novel pure compounds arising from this effort, the best will be chosen for evaluation in cultured cell assays for their effects on Praja1-related inhibition of transcription associated with bone formation. Compounds that pass screening and secondary assay evaluation will be considered for animal model evaluation after Phase II. Osteoporosis remains a major challenge to the maintenance of health and quality of life in an aging population; the most sought after treatments are those which will build up bone mass instead of merely preventing further bone loss. Progenra has developed a technology that will permit the discovery of compounds that can work in this fashion; the company proposed to look for new osteoporosis drugs in collections of pure compounds and natural products extracts from plants and marine organisms. The latter have been good sources of highly effective drugs in the past (taxol, statins, etc). [unreadable] [unreadable] [unreadable] [unreadable]